OBESITY AND NONALCOHOLIC FATTY LIVER DISEASE

肥胖和非酒精性脂肪肝

基本信息

批准号：
7407492
负责人：
Samuel Klein
金额：
$ 43.07万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1986
资助国家：
美国
起止时间：
1986-12-01 至 2010-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7407492
关键词：
3-nitrotyrosine Adipose tissue Adult Affect Albumins Apolipoproteins B Appearance Body Weight decreased Carbohydrates Cells Chronic Cirrhosis Class Condition Data Development Diet Disease Euglycemic Clamping Evaluation Fatty Acids Fatty acid glycerol esters Fibrinogen Fibrosis Fluorescence Functional disorder Glucose Glucose Clamp Goals Health Hepatic Hepatic Stellate Cell High Prevalence Histologic Immunohistochemistry Inflammation Insulin Insulin Resistance Interleukin-6 Interleukin-8 Intervention Kinetics Knowledge Lipid Peroxidation Lipids Lipolysis Lipoproteins Liver Liver Failure Liver diseases Magnetic Resonance Spectroscopy Mediator of activation protein Messenger RNA Metabolic Metabolic syndrome Metabolism Methods Muscle Necrosis Nicotinic Acids Obesity Oils Oxidative Stress Pathogenesis Patients Peripheral Blood Mononuclear Cell Persons Plasma Polymerase Chain Reaction Population Prevalence Procedures Procollagen Production Protein Biosynthesis Proteins Protocols documentation Randomized Rate Resistance Risk Factors Severities Smooth Muscle Actin Staining Method Staging Steatohepatitis Techniques Testing Therapeutic Therapeutic Intervention Time Tissues Tracer Transforming Growth Factors Tumor Necrosis Factor-alpha Tumor Necrosis Factors United States Very low density lipoprotein Week Weight bariatric surgery basal insulin base cytokine fatty acid oxidation fibrogenesis glucose metabolism glucose production human TNF protein improved insulin sensitivity non-alcoholic fatty liver novel therapeutics peripheral blood protein metabolism stable isotope stellate cell

项目摘要

DESCRIPTION (provided by applicant): Obesity is a major risk factor for non-alcoholic fatty liver disease (NAFLD), which represents a spectrum of liver diseases characterized histologically as steatosis, steatohepatitis, fibrosis and cirrhosis. NAFLD is a major health problem in the U.S. because of its high prevalence and causal relationship with serious liver abnormalities. However, the mechanism(s) responsible for developing NAFLD in obese persons and the effects of NAFLD itself on hepatic metabolic function are not known. This gap in knowledge has made it difficult to identify effective therapy. Although weight loss is generally recommended for obese patients with NAFLD, the available data suggest that rapid and marked weight loss increases inflammation, and even liver failure. The primary goal of this proposal is to provide a better understanding of: 1) the pathogenesis and pathophysiology of NAFLD in obese persons, and 2) the effect of marked weight loss on the histologic and metabolic abnormalities associated with NAFLD. We will test the following hypotheses: 1) obesity causes hepatic fat accumulation, because of excessive fatty acid release from adipose tissue and increased FFA availability, 2) increased hepatic fat content causes insulin-resistant glucose production by the liver and altered hepatic lipoprotein and protein synthesis, 3) increased hepatic fat content causes increases lipid peroxidation and hepatic oxidative stress, hepatic inflammation, necrosis and fibrosis, and 4) marked weight loss improves the histological and metabolic features of NAFLD once patients are weight stable. Two study protocols will be performed. In Protocol 1, 30 subjects with class I obesity (BMI 30-34.9 kg/m 2) and NAFLD will be randomized to 6 weeks of a low-carbohydrate, high-fat diet (to increase lipolysis and plasma FFA availability), niaspan therapy (to decrease lipolysis and plasma FFA availability), or observation (control). An additional 10 obese subjects with normal hepatic lipid content will also be treated with a low-carbohydrate, high-fat diet to determine whether excess FFA availability also increases hepatic fat in persons with normal liver. In Protocol 2, subjects with class II and III obesity (BMI 35-50 kg/m 2) will undergo gastric bypass surgery. The following metabolic evaluations will be performed before and after the interventions: 1) assessment of basal glucose and fatty acid kinetics, 2) assessment of liver, adipose tissue, muscle and insulin sensitivity during a hyperinsulinemic-euglycemic clamp procedure, 3) hepatic lipoprotein metabolism (VLDL-TG and VLDL-apolipoprotein B secretion), 4) hepatic protein (albumin, and fibrinogen) synthesis, 4) assessment of hepatic fat content by magnetic resonance spectroscopy (in Protocol 1 subjects only), and 5) liver lipid peroxidation and fibrogenesis by using immunohistochemistry. The results from these studies will lay the groundwork for the development of novel therapeutic interventions for NAFLD in obese patients.

描述（由申请人提供）：肥胖是非酒精性脂肪肝病（NAFLD）的主要危险因素，它代表了组织学上特征为脂肪变性，脂肪性肝炎，脂肪性肝炎，纤维化和肝硬化的一系列肝脏疾病。 NAFLD在美国是一个主要的健康问题，因为它与严重的肝脏异常存在高流行和因果关系。但是，尚不清楚负责肥胖者中NAFLD的机制以及NAFLD本身对肝代谢功能的影响。知识的差距使得很难识别有效的疗法。尽管通常建议患有NAFLD的肥胖患者体重减轻，但可用的数据表明，快速和明显的体重减轻会增加炎症，甚至肝衰竭。该提案的主要目的是更好地理解：1）肥胖者中NAFLD的发病机理和病理生理学，以及2）显着体重减轻对与NAFLD相关的组织学和代谢异常的影响。 We will test the following hypotheses: 1) obesity causes hepatic fat accumulation, because of excessive fatty acid release from adipose tissue and increased FFA availability, 2) increased hepatic fat content causes insulin-resistant glucose production by the liver and altered hepatic lipoprotein and protein synthesis, 3) increased hepatic fat content causes increases lipid peroxidation and hepatic oxidative stress,一旦患者体重稳定，肝发炎，坏死和纤维化以及4）体重减轻可改善NAFLD的组织学和代谢特征。将执行两个研究方案。在协议1中，有30名I级肥胖症（BMI 30-34.9 kg/m 2）和NAFLD将随机分为低碳水化合物，高脂饮食（增加脂肪分解和血浆FFA可用性），Niaspan疗法，Niaspan治疗（以减少脂肪分解和血浆FFA的可用性）。另外10名具有正常肝脂质含量的肥胖受试者还将通过低碳水化合物，高脂饮食治疗，以确定过量的FFA可用性是否还会增加肝脏正常患者的肝脂肪。在协议2中，II级和III级肥胖的受试者（BMI 35-50 kg/m 2）将接受胃旁路手术。将在干预措施之前和之后进行以下代谢评估：1）评估基础葡萄糖和脂肪酸动力学，2）评估在高胰岛素 - 糖尿病性夹具过程中肝脏组织，肌肉和胰岛素敏感性的评估肝蛋白（白蛋白和纤维蛋白原）合成，4）通过磁共振光谱法评估肝脂肪含量（仅在方案1受试者中），5）使用免疫组织化学来评估肝脂质过氧化和纤维化。这些研究的结果将为肥胖患者的NAFLD开发新的治疗干预措施奠定基础。